Perils of Estimating GFR in Patients with Cirrhosis

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In my attempt to highlight nephrology content in non-renal
journals, I will this month focus on a series of articles in Hepatology
concerning eGFR in cirrhotic patients. We are all aware of the concerns using
creatinine-based tools for estimating GFR in this patient cohort given their malnourished, low muscle-mass state. The use of Cystatin-C based equations may theoretically be more
informative as this protein is not influenced to the same degree by non-renal
factors. However, Cystatin-C is far from perfect and is influenced by sepsis,
inflammation and steroid use. Other concerns include the use of the MDRD-6
equation due to the inaccurate determination of albumin (may receive IV infusions)
and urea (increased by GI bleed/steroids) in these equations.

As liver patients
with renal dysfunction have such a poor prognosis, they are prioritized for
liver transplant by way of inclusion in the MELD score, the prognostic tool used
to allocate liver allografts. Since adopting MELD, the number of combined liver-kidney
transplants (cLKT) has continued to grow, with cLKT considered when
GFR<30mls/min and sometimes at higher eGFR. As the demand for kidneys
continues to outstrip supply, nephrologists in particular have legitimate
concerns regarding the potential for inappropriate use of precious renal
allografts in cLKT. This may occur if eGFR underestimates true GFR as may occur
with creatinine-based equations. Also concerning is overestimation of true GFR resulting
in denial of cLKT where it may actually be indicated, leading to inferior patient
outcomes. (See the post by Andrew regarding combined liver-kidney transplant allocation).

Francoz et al studied 300 patients with cirrhosis being
evaluated for transplant that had iohexol clearance measured. This was compared to MDRD-4, MDRD-6 and CKD-EPI equations (all using creatinine only)
and found that MDRD-6 was the most accurate although it did underestimate true
GFR and all 3 equations had poor correlation (R2 0.37-0.4). MDRD-4 and CKD-EPI overestimated
GFR especially in those with GFR<60mls/m.

DeSouza et al also looked at patients being evaluated
for transplant (n=202) and measured GFR using inulin clearance. Throughout all
severities of cirrhosis, Cystatin-C equations were superior with CKD-EPI (Cys-C)
the best, compared to creatinine-based MDRD & CKD-EPI methods (which significantly
over-estimated true GFR). Of note it outperformed CKD-EPI (creatinine-cystatin-C
combined).
Mindikoglu et al examined 72 outpatients with stable
cirrhosis comparing CKD-EPI (creatinine-cystatin-C combined) to 24-hour creatinine
clearance, Cockcroft-Gault equation and multiple other creatinine-based methods
including MDRD & CKD-EPI. Their gold standard was iothalamate clearance. CKD-EPI (creatinine-cystatin-C) performed
better than all others including CKD-EPI (Cys-C), unlike DeSouza et
al.
Confusing right? What we can take away from these useful
studies is that Cystatin-C based equations may be better than creatinine alone
equations (remember Francoz et al did NOT use Cystatin-C). However, it should
be noted that the diagnostic performance of the best equations in the studies was
still markedly lower than reported in validated normal populations. 
My feeling
is that in borderline cases when a cLKT is being considered, we need additional
data. I would consider a borderline case stable renal
dysfunction in the eGFR 20-50mls/min range (arbitrary I know!), not including co-existent
ESLD/ESRD or obvious acute hepatorenal cases which will recover with a
functioning liver allograft. As renal biopsy is usually not desirable in patient
with chronic liver disease, it seems sensible to actually measure GFR in these
cases. This appears to be the prudent approach to take to strike a balance
between providing a kidney to those who need it and not inadvertently denying
an organ to a wait-listed ESRD patient.

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